1. Field of the Invention
The present invention concerns methods and compositions for treating and in preferred embodiments eliminating human immunodeficiency virus (HIV) in infected subjects. In particular embodiments, the compositions and methods concern targeting molecules, such as antibodies or antibody fragments against HIV antigens, for example against HIV envelope antigen. In more particular embodiments, the antibodies or antibody fragments may be conjugated to one or more agents, such as therapeutic agents, diagnostic agents, virostatic agents and/or cytotoxic agents, including but not limited to chemotherapeutic agents such as doxorubicin. In alternative embodiments, bispecific or multispecific antibodies or fragments thereof may be used, with one or more binding sites directed towards HIV antigen(s) and one or more binding sites with affinity for a carrier molecule to which cytotoxic, virostatic or other therapeutic and/or diagnostic agents may be attached.
2. Description of Related Art
Despite encouraging advances in the treatment of human immunodeficiency virus-1 (HIV-1) with anti-retroviral therapy (ART), analyses of peripheral blood and lymph nodes have documented the presence of persistent reservoirs of resting T cells which harbor latent provirus that can activate spontaneously even years after the termination of therapy (Berger et al., Proc Natl Acad Sci USA 1998, 95:11511-11513; Blankson et al., Annu Rev Med 2002,53:557-593).
Binding and neutralizing antibodies can prevent attachment of free virus to the cellular receptor, they can bind to the viral surface, and they can induce complement-mediated virolysis of free virions (Parren et al., AIDS 1999, 13[Suppl A]:S137-162). Antibodies may also mediate killing of infected cells by antibody-dependent cellular cytotoxicity (ADCC), by coupling NK-cells to infected target cells (Broliden et al., J Virol 1990, 64:936-940). However, the use of anti-viral antibodies alone as part of an immunotherapy of patients infected with HIV has not fulfilled its initial promise (Hinkula et al., J Acquir Immune Defic Syndr 1994, 7:940-951; Trkola et al., Nat Med 2005, 11:615-622).
Attempts have been made to use various viral or cellular components as targets for antibody delivery of therapeutic agents to HIV-infected cells (Davey et al., J Infect Dis 1994, 170:1180-1188; Pincus et al., J Immunol 2003, 170:2236-2241; Ramachandran et al., J Infect Dis 1994, 170:1009-1013; Saavedra-Lozano et al., Proc Natl Acad Sci USA 2004, 101:2494-2499). Similar immunotoxins have proved promising in cancer patients (Wu and Senter, Nat Biotechnol 2005, 23:1137-1146). However, a need exists for more effective methods and compositions for treatment of HIV-infected cells.